Machine for production of solid dosage forms

ABSTRACT

In one aspect, the present invention features a machine for the production of a solid dosage form wherein the machine is adapted to form a dosage form between a first forming tool and a second forming tool within a forming cavity and wherein the first RF electrode and the second RF electrode are arranged within the machine such that when RF energy is applied between the first RF electrode and the second RF electrode, the RF energy passes through the portion of the forming cavity adapted to form the dosage form.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority of the benefits of U.S. ProvisionalApplication Ser. No. 61/640,910, filed May 1, 2012, and U.S. ProvisionalApplication Ser. No. 61/704,780, filed Sep. 24, 2012. The completedisclosure of the aforementioned related U.S. patent application ishereby incorporated by reference for all purposes.

BACKGROUND OF THE INVENTION

Pharmaceutical tablets and other confectionary compressed tablet formsare very common and widely accepted delivery vehicles for pharmaceuticalactives or powders. They provide a convenient means to compress arelatively large volume of low density powders into a smaller compactformat that is easily handled, swallowed, or chewed. Various shapes,sizes, and configurations are common in the marketplace. The vastmajority of these tablet forms are manufactured from dry blends ofcompressible powders or granulations that are then fed into rotarytablet compression machines (e.g., such as those commercially availablefrom Fette America Inc., Rockaway, N.J. or Manesty Machines LTD,Liverpool, UK). These tablet compression machines accurately dose apredefined amount of powder into a die cavity. The powder is thencompressed using punches which impinge upon the powder and compact itwithin the die cavity. The final step in the operation is to eject thefinished tablet form from the die cavity completing the manufacturingsequence. Most tablet constructions made from this process are simplesingle component forms; however these machines can sometimes be modifiedto produce more complex multi-layer tablets by adding multiple feedingand compression stations. Multi-layer tablets produced by this means areprocedure in a sequential and stepwise fashion whereby layers orsections are built up layer upon layer. Each layer requires anadditional dosing assembly punches and an additional compressionassembly. Since these machines have a relatively massive constructiondue to the very high compaction forces required to get formulations tocompact properly (machines capable of producing up to 20,000 poundsforce are quite common) multi-layer machines can become very expensiveand hard to maintain. An additional drawback to producing tablets inthis fashion is the limitations of the layered geometry. Regions of atablet with an orientation that is perpendicular to the tablet ejectiondirection are extremely hard to produce and would require more elaborateand complex modifications.

A further drawback to the layer upon sequence of tablet manufacturing isspecific to the production of orally disintegrating tablets. Thesetablets require a low density and highly porous tablet constructionwhereby saliva of the mouth quickly penetrates the tablet to break downthe particle bonds to create a fast dissolve effect. The layer uponlayer approach requires that a first layer of powdered material is firstfilled into a die cavity with the surface of the die cavity beingscraped to establish the required volume of fill. This first fill layeris then compressed with a punch to a controlled depth of penetrationinto the die cavity. This depth of penetration must be preciselycontrolled and the powder must be uniformly compacted to create acontrolled volume for the second fill of powder material. The next stepof the operation is to fill this newly created volume with a secondpowder. This powder is then scraped flush with top surface of the diecavity and the final step is to compact the second layer upon the firstlayer a second time with a punch which presses upon both layers of thetablet. This double compaction smashes the tiny air pockets betweenparticles causing a detrimental effect to the porous structure that isdesired for the orally disintegrating tablet. In pharmaceuticalmanufacturing it is not possible to skip this double compression stepbecause a dense uniform first layer is a prerequisite to achievingaccurate dosing of the powdered medicament of the second layer. Accuratedosing of drugs by pharmaceutical manufacturers is critical tomaintaining the health and safety of patients.

SUMMARY OF THE INVENTION

In one aspect, the present invention features a machine for theproduction of a solid dosage form, the machine including: (a) a dieblock having one or more forming cavities each having an inner wall, afirst opening at the surface of one side of the die block, and a secondopening at the surface on the opposite side of the die block; (b) one ormore first dosing nozzle adapted to both measure an amount of a firstpowder blend and discharge the measured amount of the first powder blendwithin one of the one or more forming cavity; (d) one or more firstforming tools each adapted to move into one of the cavities through thefirst opening of the forming cavity; (e) one or more second formingtools each adapted to move adjacent to one of the second openings orinto one of the cavities through the second opening of the formingcavity; (f) at least one first RF electrode operably associated with theone or more first forming tools, the one or more second forming tools,or the inner wall of the one or more forming cavities; and (g) at leastone second RF electrode operably associated with the one or more firstforming tools, the one or more second forming tools, or the inner wallof the one or more forming cavities; wherein the machine is adapted toform a dosage form between a first forming tool and a second formingtool within a forming cavity and wherein the first RF electrode and thesecond RF electrode are arranged within the machine such that when RFenergy is applied between the first RF electrode and the second RFelectrode, the RF energy passes through the portion of the formingcavity adapted to form the dosage form.

In another aspect, the present invention features a machine for theproduction of a solid dosage form, the machine including: (a) a dieblock having one or more forming cavities each having an inner wall, afirst opening at the surface of one side of the die block, and a secondopening at the surface on the opposite side of the die block; (b) one ormore first dosing nozzles adapted to both measure an amount of a firstpowder blend and discharge the measured amount of the first powder blendwithin one of the one or more forming cavity; (c) one or more seconddosing nozzles adapted to both measure an amount of a second powderblend and discharge the measured amount of the second powder blendwithin one of the one or more forming cavity; (d) one or more firstforming tools each adapted to move into one of the cavities through thefirst opening of the forming cavity; (e) one or more second formingtools each adapted to move adjacent to one of the second openings orinto one of the cavities through the second opening of the formingcavity; (f) at least one first RF electrode operably associated with theone or more first forming tools, the one or more second forming tools,or the inner wall of the one or more forming cavities; and (g) at leastone second RF electrode operably associated with the one or more firstforming tools, the one or more second forming tools, or the inner wallof the one or more forming cavities; wherein the machine is adapted toform a dosage form between a first forming tool and a second formingtool within a forming cavity and wherein the first RF electrode and thesecond RF electrode are arranged within the machine such that when RFenergy is applied between the first RF electrode and the second RFelectrode, the RF energy passes through the portion of the formingcavity adapted to form the dosage form.

In another aspect, the present invention features a machine for theproduction of a solid dosage form, the machine including: (a) a dieblock having one or more forming cavities each having an inner wall, afirst opening at the surface of one side of the die block, and a secondopening at the surface on the opposite side of the die block, whereinthe forming cavity further includes a movable divider adapted to form afirst chamber and a second chamber within the forming cavity; (b) one ormore first dosing nozzle adapted to both measure an amount of a firstpowder blend and discharge the measured amount of the first powder blendwithin one of the first chamber; (c) one or more second dosing nozzleadapted to both measure an amount of a second powder blend and dischargethe measured amount of the second powder blend within one of the secondchamber; (d) one or more first forming tools each adapted to move intoone of the cavities through the first opening of the forming cavity; (e)one or more second forming tools each adapted to move adjacent to one ofthe second openings or into one of the cavities through the secondopening of the forming cavity; (f) at least one first RF electrodeoperably associated with the one or more first forming tools, the one ormore second forming tools, or the inner wall of the one or more formingcavities; and (g) at least one second RF electrode operably associatedwith the one or more first forming tools, the one or more second formingtools, or the inner wall of the one or more forming cavities; whereinthe machine is adapted to remove the movable divider from within theforming cavity such that the first powder blend contacts the secondpowder blend within the forming cavity and wherein the first RFelectrode and the second RF electrode are arranged within the machinesuch that when RF energy is applied between the first RF electrode andthe second RF electrode, the RF energy passes through the portion of theforming cavity adapted to form the dosage form.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-G are perspective views of multi-region tablets.

FIG. 2A is an overhead view of multi-component tablet machine 200.

FIG. 2B is a perspective view of multi-component tablet machine 200.

FIGS. 3A-3B are cross sections of dosing module 14 over first powdertray 15.

FIG. 4A is a cross section of dosing module 14 over first powder tray15.

FIG. 4B-4C is a perspective view of dosing module 14 moving from thefirst powder tray 15 to second powder tray 16.

FIGS. 5A-5B are cross sections of dosing module 14 over second powdertray 16.

FIG. 6A is a cross section of dosing module 14 over second powder tray16.

FIG. 6B is a perspective view of dosing module 14 moving from the secondpowder tray 16 to a position over the die block 19.

FIGS. 7A and 7C are cross sections of dosing module 14 over die block19.

FIG. 7B is a perspective view of a portion of die block 19, forming tool20, and a portion of the nozzles 3 and 4.

FIGS. 8A-8B are cross sections of dosing module 14 over die block 19.

FIG. 9 is a perspective view of forming station 202.

FIG. 10 is a cross section showing movable electrode plate 340 andmovable electrode plate 341 in an open position.

FIG. 11 is a cross section showing movable electrode plate 340 andmovable electrode plate 341 in a closed position.

FIG. 12A is a cross section showing forming tools 420 and 421 withattachments 440 and 430 made of RF energy insulative material.

FIGS. 12B and 12C is a cross section of tablet ejection station 203.

FIGS. 13A-C are a perspective view of various embodiment of dividerplates.

FIG. 14A is a perspective view of outer dosing nozzle 630 and innerdosing nozzle 631.

FIG. 14B-J are cross sections of outer dosing nozzle 630 and innerdosing nozzle 631.

FIG. 15A is an overhead view of multi-component tablet machine 1500.

FIG. 15B is a perspective view of multi-component tablet machine 1500.

FIGS. 16A-16B are cross sections of dosing module 714 over first powdertray 15.

FIG. 17A is a cross section of dosing module 714 over first powder tray15.

FIG. 17B is a perspective view of dosing module 714 moving from thefirst powder tray 15 to a position over the die block 19.

FIGS. 18A and 18B are cross sections of dosing module 714 over die block19.

FIG. 19 is a perspective view of forming station 202.

FIG. 20 is a cross section showing movable electrode plate 340 andmovable electrode plate 341 in an open position.

FIG. 21 is a cross section showing movable electrode plate 340 andmovable electrode plate 341 in a closed position.

FIGS. 22A and 22B are a cross section of tablet ejection station 203.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments can be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified.

As discussed above, in one aspect, the present invention features In oneaspect, the present invention features a machine for the production of asolid dosage form, the machine including: (a) a die block having one ormore forming cavities each having an inner wall, a first opening at thesurface of one side of the die block, and a second opening at thesurface on the opposite side of the die block; (b) one or more firstdosing nozzle adapted to both measure an amount of a first powder blendand discharge the measured amount of the first powder blend within oneof the one or more forming cavity; (d) one or more first forming toolseach adapted to move into one of the cavities through the first openingof the forming cavity; (e) one or more second forming tools each adaptedto move adjacent to one of the second openings or into one of thecavities through the second opening of the forming cavity; (f) at leastone first RF electrode operably associated with the one or more firstforming tools, the one or more second forming tools, or the inner wallof the one or more forming cavities; and (g) at least one second RFelectrode operably associated with the one or more first forming tools,the one or more second forming tools, or the inner wall of the one ormore forming cavities; wherein the machine is adapted to form a dosageform between a first forming tool and a second forming tool within aforming cavity and wherein the first RF electrode and the second RFelectrode are arranged within the machine such that when RF energy isapplied between the first RF electrode and the second RF electrode, theRF energy passes through the portion of the forming cavity adapted toform the dosage form.

While the specific embodiments herein focus on tablets, other dosageforms such as lozenges and chewing gums can also be made by such machineand process.

Powder Blend

In one embodiment, the tablet is manufactured by applying energy to apowder blend containing at least one pharmaceutically active agent (asdiscussed herein) and, optionally, at least one first material (asdiscussed herein), at least one second material (as discussed herein),at least one meltable binder (as discussed herein), and/or othersuitable excipients.

In one embodiment, the powder blend has a density of less than about 0.5g/cc, such as less than about 0.4 g/cc, such as less than about 0.3g/cc. In one embodiment, the powder blend is substantially free ofliquid material (e.g., less than 1%, such as less than 0.5%, such asless than 0.01%, such as 0%).

In one embodiment, the powder blend contains at least one first materialand at least one second material. In one embodiment, the at least onepharmaceutically active agent are contained within particles, such aspolymer-coated particles. In one embodiment, the total amount of suchparticles, the at least one first material, and the at least one secondmaterial include at least 90%, by weight, of the powder blend/tablet,such as at least 95%, such as at least 98%, by weight of the powderblend/tablet.

In one embodiment, the powder blend/tablet includes at least 60%, byweight, of the at least one first material and the at least one secondmaterial, such as at least 75%, such as at least 90%. In one embodiment,the ratio of the at least one first material to the at least one secondmaterial is from about 20:80 to about 70:30, such as from about 25:75 toabout 60:40, such as about 35:65 to about 45:55.

Examples of suitable excipients include, but are not limited to,lubricants, glidants, sweeteners, flavor and aroma agents, antioxidants,preservatives, texture enhancers, colorants, and mixtures thereof. Oneor more of the above ingredients may be present on the same particle ofthe powder blend.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicondioxide. Examples of sweeteners for the present inventions include, butare not limited to high intensity sweeteners such as synthetic ornatural sugars; artificial sweeteners such as saccharin, sodiumsaccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose,dihydrochalcone, alitame, miraculin, monellin, and stevside.

Examples of flavors and aromatics include, but are not limited to,essential oils including distillations, solvent extractions, or coldexpressions of chopped flowers, leaves, peel or pulped whole fruitcontaining mixtures of alcohols, esters, aldehydes and lactones;essences including either diluted solutions of essential oils, ormixtures of synthetic chemicals blended to match the natural flavor ofthe fruit (e.g., strawberry, raspberry and black currant); artificialand natural flavors of brews and liquors, e.g., cognac, whisky, rum,gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint;fruit juices including expelled juice from washed, scrubbed fruits suchas lemon, orange, and lime; spear mint, pepper mint, wintergreen,cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseedsnuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts),almonds, raisins; and powder, flour, or vegetable material partsincluding tobacco plant parts, e.g., genus Nicotiana, in amounts notcontributing significantly to the level of nicotine, and ginger.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.

Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

Examples of texture enhancers include, but are not limited to, pectin,polyethylene oxide, and carrageenan, and mixtures thereof. In oneembodiment, texture enhancers are used at levels of from about 0.1% toabout 10% percent by weight.

In one embodiment of the invention, the powder blend has an averageparticle size of less than 500 microns, such as from about 50 microns toabout 500 microns, such as from about 50 microns and 300 microns.Particles in this size range are particularly useful for directcompacting processes.

In one embodiment, the powder blend is substantially free ofpolyethylene glycols, hydrated cellulose polymers, gums (such as xanthangum and carrageenans), and gelatins. As used herein, what is meant by“substantially free” is less than 5%, such as less than 1%, such as lessthan 0.1%, such as completely free (e.g., 0%). Such a composition isadvantageous for maintaining an immediate release dissolution profile,minimizing processing and material costs, and providing for optimalphysical and chemical stability of the tablet.

In one embodiment, the powder blend/tablet is substantially free ofdirectly compressible water insoluble fillers. Water insoluble fillersinclude but are not limited to microcrystalline cellulose, directlycompressible microcrystalline cellulose, celluloses, water insolublecelluloses, starch, cornstarch and modified starches. As described inthis embodiment, substantially free is less than 2 percent, e.g. lessthan 1 percent or none.

In one embodiment, the powder blend is substantially free of superdisintegrants. Super disintegrants include cross carmellose sodium,sodium starch glycolate, and cross-linked povidone. A compositionsubstantially free of super-disintegrants is advantageous for enhancingmouth-feel and tablet stability due to reduced water absorbance.

In one embodiment, at least 90%, by weight, of the tablet is comprisedof material having a melting point greater than 60° C., such as at least70° C., such as at least 80° C.

First Material

The powder blend/tablet of the present invention includes at least onefirst material which is a dielectric water-containing material (i)including from about 1 to about 5 percent, by weight, of bound water,such as from about 1.5 to about 3.2 percent, by weight, of bound water,such as from about 1.7 to about 3 percent, by weight of bound water and(ii) has a dielectric loss, when measured at a density of between 0.15and 0.5 g/cc, of from about 0.05 to about 0.7, such as from about 0.1 toabout 0.5, such as 0.25 to about 0.5.

In one embodiment, the first material is a starch. Examples of suchstarches include, but are not limited to, hydrolyzed starches such asmaltodextrin and corn syrup solids. Such starches may be sourced from avariety of vegetable sources, such as grain, legume, and tuber, andexamples include, but are not limited to, starches sourced from corn,wheat, rice, pea, bean, tapioca and potato.

In one embodiment, the first material when added to the powder blend hasa bulk density of less than about 0.4 g/cc, such as less than about 0.3g/cc, such as less than 0.2 g/cc.

In one embodiment, the average particle size of the first material isless than 500 microns, such as less than 150 microns.

The first material(s) may be present at level of at least about 15percent, by weight, of the tablet, such as at least about 20 percent,such as from about 20 percent to about 45 percent of the powderblend/tablet, such as from about 20 percent to about 42 of the powderblend/tablet, such as from about 20 percent to about 40 of the powderblend/tablet.

Second Material

In one embodiment, the powder blend/tablet of the present inventionincludes at least one second material (i) having a water solubility fromabout 20 to about 400 g per 100 g of water at 25° C., (ii) having adielectric loss, when measured at a density between 0.5 and 1.1 g/cc, ofless than about 0.05, such as less than about 0.01, such as less than0.005, such as about 0. In one embodiment, the second material iscrystalline at 25° C.

In one embodiment, the second material is a sugar or an alcohol orhydrate thereof. Examples of sugars include, but are not limited to,monosaccharides and disaccharides such as sucrose, fructose, maltose,dextrose, and lactose, and alcohols and hydrates thereof.

Examples of sugar alcohols include, but are not limited to, erythritol,isomalt, mannitol, maltitol, lactitol, sorbitol, and xylitol.

The second material(s) may be present at level of about 18 percent toabout 72 percent of the powder blend/tablet, such as from about 20percent to about 64 percent of the powder blend/tablet, such as fromabout 39 percent to about 56 percent of the powder blend/tablet.

Meltable Binder

In one embodiment, the powder blend/tablet of the present inventionincludes at least one meltable binder. In one embodiment, the meltablebinder has a melting point of from about 40° C. to about 140° C., suchas from about 55° C. to about 100° C. The softening or melting of themeltable binder(s) results in the sintering of the tablet shape throughthe binding of the softened or melted binder with the pharmaceuticallyactive agent and/or other ingredients within the compacted powder blend.

In one embodiment, the meltable binder is a RF-meltable binder. What ismeant by an RF-meltable binder is a solid binder that can be softened ormelted upon exposure to RF energy. The RF-meltable binder typically ispolar and has the capability to re-harden or resolidify upon cooling.

In one embodiment, the meltable binder is not a RF-meltable binder. Insuch embodiment, the powder blend contains an excipient that heats uponexposure to RF energy (e.g., a polar excipient), such that the resultingheat from is able to soften or melt the meltable binder. Examples ofsuch excipients include, but are not limited to, polar liquids such aswater and glycerin; powdered metals and metal salts such as powderediron, sodium chloride, aluminum hydroxide, and magnesium hydroxide;stearic acid; and sodium stearate.

Examples of suitable meltable binders include: fats such as cocoabutter, hydrogenated vegetable oil such as palm kernel oil, cottonseedoil, sunflower oil, and soybean oil; mono, di, and triglycerides;phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermacetiwax, beeswax, candelilla wax, shellac wax, microcrystalline wax, andparaffin wax; water soluble polymers such as polyethylene glycol,polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides; polyethylene oxides; and sucroseesters.

In one embodiment, the meltable binder is a RF-meltable binder, and theRF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000. Aparticularly preferred RF-meltable binder is PEG having at least 95% byweight of the PEG particles less than 100 microns (as measured byconventional means such as light or laser scattering or sieve analysis)and a molecular weight between 3000 and 8000 Daltons.

The meltable binder(s) may be present at level of about 0.01 percent toabout 70 percent of the powder blend/tablet, such as from about 1percent to about 50 percent, such as from about 10 percent to about 30percent of the powder blend/tablet.

Carbohydrate

In one embodiment, the powder blend/tablet contains at least onecarbohydrate in addition to any first material, second material, ormeltable binder that is also a carbohydrate. In one embodiment, thepowder blend/tablet contains both a meltable binder and a carbohydrate.The carbohydrate can contribute to the dissolvability and mouth feel ofthe tablet, aid in distributing the other ingredients across a broadersurface area, and diluting and cushioning the pharmaceutically activeagent. Examples of carbohydrates include, but are not limited to,water-soluble compressible carbohydrates such as sugars (e.g., dextrose,sucrose, maltose, isomalt, and lactose), starches (e.g., corn starch),sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol,lactitol, and xylitol), and starch hydrolysates (e.g., dextrins, andmaltodextrins).

The carbohydrate(s) may be present at level of about 5 percent to about95 percent of the powder blend/tablet, such as from about 20 percent toabout 90 percent or from about 40 percent to about 80 percent of thepowder blend/tablet. When a meltable binder is contained within thepowder blend, the particle size of the of carbohydrate can influence thelevel of meltable binder used, wherein a higher particle size ofcarbohydrate provides a lower surface area and subsequently requires alower level of meltable binder. In one embodiment, wherein thecarbohydrate(s) is greater than 50% by weight of the powder blend andthe mean particle size of the carbohydrate(s) is greater than 100microns, then the meltable binder is from about 10 to about 30 percentby weight of the powder blend/tablet.

Pharmaceutically Active Agent

The powder blend/tablet of the present invention includes at least onepharmaceutically active agent containing particles. What is meant by a“pharmaceutically active agent” is an agent (e.g., a compound) that ispermitted or approved by the U.S. Food and Drug Administration, EuropeanMedicines Agency, or any successor entity thereof, for the oraltreatment of a condition or disease. Suitable pharmaceutically activeagents include, but are not limited to, analgesics, anti-inflammatoryagents, antipyretics, antihistamines, antibiotics (e.g., antibacterial,antiviral, and antifungal agents), antidepressants, antidiabetic agents,antispasmodics, appetite suppressants, bronchodilators, cardiovasculartreating agents (e.g., statins), central nervous system treating agents,cough suppressants, decongestants, diuretics, expectorants,gastrointestinal treating agents, anesthetics, mucolytics, musclerelaxants, osteoporosis treating agents, stimulants, nicotine, andsedatives.

Examples of suitable gastrointestinal treating agents include, but arenot limited to: antacids such as aluminum-containing pharmaceuticallyactive agents (e.g., aluminum carbonate, aluminum hydroxide,dihydroxyaluminum sodium carbonate, and aluminum phosphate),bicarbonate-containing pharmaceutically active agents,bismuth-containing pharmaceutically active agents (e.g., bismuthaluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate,and bismuth subnitrate), calcium-containing pharmaceutically activeagents (e.g., calcium carbonate), glycine, magnesium-containingpharmaceutically active agents (e.g., magaldrate, magnesiumaluminosilicates, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, and magnesium trisilicate),phosphate-containing pharmaceutically active agents (e.g., aluminumphosphate and calcium phosphate), potassium-containing pharmaceuticallyactive agents (e.g., potassium bicarbonate), sodium-containingpharmaceutically active agents (e.g., sodium bicarbonate), andsilicates; laxatives such as stool softeners (e.g., docusate) andstimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such asfamotidine, ranitidine, cimetadine, and nizatidine; proton pumpinhibitors such as omeprazole, dextansoprazole, esomeprazole,pantoprazole, rabeprazole, and lansoprazole; gastrointestinalcytoprotectives, such as sucraflate and misoprostol; gastrointestinalprokinetics such as prucalopride; antibiotics for H. pylori, such asclarithromycin, amoxicillin, tetracycline, and metronidazole;antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate,and loperamide; glycopyrrolate; analgesics, such as mesalamine;antiemetics such as ondansetron, cyclizine, diphenyhydroamine,dimenhydrinate, meclizine, promethazine, and hydroxyzine; probioticbacteria including but not limited to lactobacilli; lactase;racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g.,dimethicone and simethicone, including those disclosed in U.S. Pat. Nos.4,906,478, 5,275,822, and 6,103,260); isomers thereof; andpharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyreticsinclude, but are not limited to, non-steroidal anti-inflammatory drugs(NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen,ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen)and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylicacid; acetic acid derivatives such as indomethacin, diclofenac,sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid,meclofenamic acid, and flufenamic acid; biphenylcarbodylic acidderivatives such as diflunisal and flufenisal; and oxicams such aspiroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; andpharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants, include, but are notlimited to, bromopheniramine, chlorcyclizine, dexbrompheniramine,bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine,pripolidine, ephedrine, phenylephrine, pseudoephedrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine,naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine,clemastine, acrivastine, promethazine, oxomemazine, mequitazine,buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide,xylomeazoline, loratadine, desloratadine, and cetirizine; isomersthereof; and pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include, but are notlimited to, diphenhydramine, dextromethorphan, noscapine, clophedianol,menthol, benzonatate, ethylmorphone, codeine, acetylcysteine,carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, andguaifenesin; isomers thereof; and pharmaceutically acceptable salts andprodrugs thereof.

Examples of muscle relaxants include, but are not limited to,cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, andmethocarbamol; isomers thereof; and pharmaceutically acceptable saltsand prodrugs thereof.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to sleep aids such asantihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of appetite suppressants include, but are not limited to,phenylpropanolamine, phentermine, and diethylcathinone, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of anesthetics (e.g., for the treatment of sore throat)include, but are not limited to dyclonine, benzocaine, and pectin andpharmaceutically acceptable salts and prodrugs thereof.

Examples of suitable statins include but are not limited to atorvastin,rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin,pravastatin and pharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent contained withinthe tablet is selected from phenylephrine, dextromethorphan,pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine,ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calciumcarbonate, simethicone, chlorpheniramine, methocarbomal, chlophedianol,ascorbic acid, pectin, dyclonine, benzocaine and menthol, andpharmaceutically acceptable salts and prodrugs thereof.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of pharmaceutically acceptablesalts, such as acidic/anionic or basic/cationic salts. Pharmaceuticallyacceptable acidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide. Pharmaceutically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of prodrugs of thepharmaceutically active agents. In general, such prodrugs will befunctional derivatives of the pharmaceutically active agent, which arereadily convertible in vivo into the required pharmaceutically activeagent. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, theinvention provides the esters, amides, and other protected orderivatized forms of the described compounds.

Where the pharmaceutically active agents according to this inventionhave at least one chiral center, they may accordingly exist asenantiomers. Where the pharmaceutically active agents possess two ormore chiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore, someof the crystalline forms for the pharmaceutically active agents mayexist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the pharmaceutically activeagents may form solvates with water (e.g., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In one embodiment, the pharmaceutically active agent or agents arepresent in the tablet in a therapeutically effective amount, which is anamount that produces the desired therapeutic response upon oraladministration and can be readily determined by one skilled in the art.In determining such amounts, the particular pharmaceutically activeagent being administered, the bioavailability characteristics of thepharmaceutically active agent, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.

The pharmaceutically active agent may be present in various forms. Forexample, the pharmaceutically active agent may be dispersed at themolecular level, e.g. melted, within the tablet, or may be in the formof particles, which in turn may be coated or uncoated. If thepharmaceutically active agent is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 to about 500 microns. In one embodiment, such particles arecrystals having an average particle size of from about 1 to about 300microns.

The pharmaceutically active agent may be present in pure crystal form orin a granulated form prior to the addition of the taste masking coating.Granulation techniques may be used to improve the flow characteristicsor particle size of the pharmaceutically active agents to make it moresuitable for compaction or subsequent coating. Suitable binders formaking the granulation include but are not limited to starch,polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose,and hydroxypropylcellulose. The particles including pharmaceuticallyactive agent(s) may be made by cogranulating the pharmaceutically activeagent(s) with suitable substrate particles via any of the granulationmethods known in the art. Examples of such granulation method include,but are not limited to, high sheer wet granulation and fluid bedgranulation such as rotary fluid bed granulation.

If the pharmaceutically active agent has an objectionable taste, thepharmaceutically active agent may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked pharmaceutically active agents may also be employed. For example,acetaminophen particles, which are encapsulated with ethylcellulose orother polymers by a coacervation process, may be used in the presentinvention. Coacervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio).

In one embodiment, the tablet incorporates modified release coatedparticles (e.g., particles containing at least one pharmaceuticallyactive agent that convey modified release properties of such agent). Asused herein, “modified release” shall apply to the altered release ordissolution of the active agent in a dissolution medium, such asgastrointestinal fluids. Types of modified release include, but are notlimited to, sustained release or delayed release. In general, modifiedrelease tablets are formulated to make the active agents(s) availableover an extended period of time after ingestion, which thereby allowsfor a reduction in dosing frequency compared to the dosing of the sameactive agent(s) in a conventional tablet. Modified release tablets alsopermit the use of active agent combinations wherein the duration of onepharmaceutically active agent may differ from the duration of anotherpharmaceutically active agent. In one embodiment the tablet contains onepharmaceutically active agent that is released in an immediate releasemanner and an additional active agent or a second portion of the sameactive agent as the first that is modified release.

Examples of swellable, erodible hydrophilic materials for use as arelease modifying excipient for use in the modified release coatinginclude water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, and gelling starches. Examples of water swellable cellulosederivatives include sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examplesof polyalkylene glycols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkylene oxides include poly (ethyleneoxide). Examples of acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, andhigh-molecular weight cross-linked acrylic acid homopolymers andcopolymers.

Suitable pH-dependent polymers for use as release-modifying excipientsfor use in the modified release coating include: enteric cellulosederivatives such as hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, and cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as polyvinylacetate phthalate, cellulose acetatephthalate, and acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2 (available fromRohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylicacid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH underthe tradename EUDRAGIT L).

In one embodiment the pharmaceutically active agent is coated with acombination of a water insoluble film forming polymer (such as but notlimited to cellulose acetate or ethylcellulose) and a water solublepolymer (such as but not limited to povidone, polymethacrylicco-polymers such as those sold under the tradename Eudragit E-100 fromRohm America, and hydroxypropylcellulose). In this embodiment, the ratioof water insoluble film forming polymer to water soluble polymer is fromabout 50 to about 95 percent of water insoluble polymer and from about 5to about 50 percent of water soluble polymer, and the weight percent ofthe coating by weight of the coated taste-masked particle is from about5 percent to about 40 percent. In one embodiment, the coating which isused in the coated particle of the pharmaceutically active agent issubstantially free of a material (such as polyethylene glycol) whichmelts below 85° C., in order to prevent damage to the integrity of thecoating during the RF heating step.

In one embodiment, one or more pharmaceutically active agents or aportion of the pharmaceutically active agent may be bound to an ionexchange resin for the purposes of taste-masking the pharmaceuticallyactive agent or delivering the active in a modified release manner.

In one embodiment, the pharmaceutically active agent is capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In one embodiment, the dissolutioncharacteristics of the pharmaceutically active agent within the tabletmeets USP specifications for immediate release tablets including thepharmaceutically active agent. For example, for acetaminophen tablets,USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the acetaminophen contained in thetablet is released there from within 30 minutes after dosing, and foribuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer,using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofencontained in the tablet is released there from within 60 minutes afterdosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In anotherembodiment, the dissolution characteristics of the pharmaceuticallyactive agent are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like.

In one embodiment, the pharmaceutically active agent(s) are comprisedwithin polymer-coated particles (e.g., taste-masked and/or sustainedrelease coated particles).

In one embodiment, the particles including the pharmaceutically activeagents(s) may be present at level from about 10% to about 40%, by weightof the tablet/powder blend, such as 15% to about 35%, by weight of thetablet/powder blend, such as 20% to about 30%, by weight of thetablet/powder blend. In one embodiment, the particles including thepharmaceutically active agents(s) may be present at level of at leastabout 15%, by weight, of the powder blend/tablet, such as at least about20%, by weight, of the powder blend/tablet.

Multi-Region Tablet

The multi-region tablets contain two or more regions that havedistinctly different physical compositions such as shown in FIGS. 1A-1G.In one embodiment, each region of the tablet has a unique function orsensory attribute. An example of this is a tablet constructed with acomponent region having a fast dissolve orally disintegratingcomposition and an adjacent component region having a formulation thathas a slow dissolve lozenge like composition. Alternatively a tablet canbe constructed with separate component regions containing distinctlydifferent pharmaceutical actives such as a first component containing apain relieving medicament such as acetaminophen or ibuprofen and asecond component region containing upper respiratory medicament such asdecongestants such as phenylephrine or pseudoephedrine or antihistaminessuch as diphenhydramine or cetirizine. Similarly, a tablet can bemanufactured with a composition having an immediate release medicamentcombined with a component having a controlled release medicament. In analternate embodiment, tablets can also be constructed with multiplecomponent regions of similar composition and functionality, but havingdiffering aesthetic attributes such as color, taste, or texture.

In one embodiment, the second region has a higher density than the firstregion. In one embodiment, the density of the second region is at least10% greater than the density of the first region. In one embodiment, thesecond region is a lozenge. In the embodiment wherein the second regionis a lozenge, the region (e.g., the powder blend used to create theregion) contains at least one amorphous carbohydrate polymer. What ismeant by an “amorphous carbohydrate polymer” is a molecule having aplurality of carbohydrate monomers wherein such molecule has acrystallinity of less than 20%, such as less than 10%, such as less than5%. Examples of amorphous carbohydrate polymers include, but are notlimited to hydrogenated starch hydrosolate, polydextrose, andoligosaccharides. Examples of oligosaccharides include, but are notlimited to, fructo-oligosaccharide, galacto-oligosaccharidemalto-oligosaccharide, inulin, and isolmalto-oligosaccharide.

In one embodiment, the interface between the regions is along at leastone of the major faces of the tablet. In one embodiment, the interfaceis along two major faces of the tablet (e.g., the interface extendsthrough the tablet).

A tablet with two such component regions is shown in FIG. 1A. In thisillustration, tablet 100 has a first major face 107, a second major face108, and a side wall 109. The tablet is composed of first region 101 andadjacent second region 102. The interface 103 separating the regions isa straight line in this tablet configuration. The first region 101 andsecond region 102 can have a similar appearance which would make theinterface 103 indistinguishable from the rest of the tablet. However, ina preferred embodiment of the invention, the first region 101 and secondregion 102 can have different colors, different textures, and/ordifferent optical properties, such as opaqueness or transparency tocreate a visually noticeable interface 103.

The novelty of the current invention lies not only in the multicomponent construction of the tablet, but also in the fact that thecomponent regions of the tablet have interfaces that are parallel to thetablet side walls 104 which are shown in the vertical orientation inFIG. 1A. In compression based tablet manufacturing technologies thesewalls are linear and parallel in order to facilitate the ejection of thetablet from the cavity which forms the tablet during the manufacturingprocess. The tablets are slid out of the forming cavity in a linearfashion. Tablets produced by existing technologies such as bi-layertablets produced on machines manufactured by Korsch America Inc. (SouthEaston, Mass.) and Fette Compacting America (Rockaway, N.J.) can havemultiple regions, however they require a sequential layer upon layerconstruction with interfaces which are generally perpendicular to thedie wall. In one embodiment, the present invention allows for themanufacture of a tablet possessing an interface between two or moreregions that is parallel to the die wall.

Another novel aspect of the current invention is that the regioninterfaces can be produced to have curvilinear as well as lineargeometries that can be configured to achieve unique visual or functionaleffects. This is illustrated in FIG. 1B where the interface 114 betweenfirst region 112 and second region 113 is a wavy, curvilinear line. FIG.1C illustrates a tablet with an arc shaped interface 115. FIG. 1Dillustrates a tablet having a first region 117 and a second region 118that has a blended interface region 119. In this embodiment, theinterface is not a crisp line, but rather a region of intermingledpowder formulation offering a unique aesthetic. FIG. 1E represents afurther variation where a tablet where a first region 122 is fullysurrounded by a second region 121 with a circular interface 122, thusforming a bulls eye geometry. The tablets describes so far have all hadtwo regions, however, three or more regions can also be used. FIG. 1Fshows just such a tablet with first region 124, second region 125, andthird region 126. FIG. 1G illustrates a three component tablet wherefirst region 128 and second region 130 are separated by a barrier region129. With this tablet contraction, incompatible or reactive drugproducts can be separated from each other with a barrier component.

The embodiments disclosed all offer unique tablet aesthetics which canbe used as a tablet identifier to help distinguish one medicament fromanother. The more unique and distinctive the tablet, the less likely itis to mistakenly ingest the wrong drug.

Manufacturing Method for Multi-Region Tablets

In one aspect, the present invention features a machine capable ofproducing multi-region tablet wherein the interface between the firstregion and the second region is along a major face of the tablet. Oneembodiment of such a machine is depicted in FIGS. 2A and 2B. FIG. 2Aillustrates a plan view of an embodiment of this invention, and FIG. 2Billustrates a three dimensional view of this embodiment. Multi-regiontablet machine 200 is composed of four major assemblies; namely powderdosing station 201, rotary table assembly 204, forming station 202, andtablet ejection station 203.

The powder dosing station 201 is designed to accurately dose multiplepowder blends. It is comprised of a first powder blend tray 15 whichcontains powder blend bed 1 and second powder blend tray 16 whichcontains powder blend bed 2. Powder blends are fed into the first powderblend tray 15 and second powder blend tray 16 through feed hoppers 27and 28, respectively. The dosing head assembly 13 is positioned over thepowder blend beds 1 and 2 as well as over the rotary table assembly 204.In a preferred embodiment, the dosing head assembly 13 is comprised ofthree identical dosing modules 14 arrayed radially from a central hub11. In this embodiment, the rotary dose head assembly sequentiallyindexes first over powder blend bed 1 to obtain a volume of powder blendfrom powder blend bed 1. It then indexes over powder blend bed 2 toobtain a volume of powder blend from powder blend bed 2. It then indexesto discharge the two powder blend volumes 1 b and 2 b into die block 19on dial plate 22 (as shown in FIG. 8A), which indexes between the powderdosing station 201, forming station 202, and tablet ejection station203. Although two powder blend volumes are illustrated here, the dosingof three or more separate powder blend volumes could be performed withadditional powder blend beds and, optionally, additional dose headassemblies.

In one embodiment, the powder blend beds 1 and 2 are fluffed to helpmaintain a uniform density and to prevent densification of the powderbed. In one embodiment powder blend trays 15 and 16 rotate while angledblending blade 24 remains stationary, causing powder blend beds 1 and 2to move up and over the angled blending blade 24. The subsequent liftingand dropping of the powder blend over the trailing edge of the blendingblade 24 causes the powder particles to separate and un-clump as theyfree fall back to the powder blend bed. The angle of blending blade 24is controlled to achieve varying drop distances thereby achieving thedesired fluffing action. Since the powder blend beds 1 and 2 arecircular and since the tangential velocity at any point on the powderblend beds 1 and 2 varies according to its radius, the blade can have ageometry that tapers along its access to account for velocity variationsalong the radius of the beds. A twisting geometry can also beincorporated into the blending blade 24 to control the lift distance andduration at various points along the radius of the powder blend beds. Inanother embodiment (not shown), a series of angled blending blades canbe placed at various locations within the powder blend bed in anorientation that is perpendicular to the bed. These blades are arrangedat various angles to move powder blend from the outer radius of thepowder blend bed to the inner radius or vise versa. This mixing effectis also useful in dealing with the tangential velocity effect justdescribed. In another embodiment, powder blend beds 1 and 2 remainstationary, and a rotating arm (not shown) within first powder blendtrays 15 and 16 mixes powder blend beds 1 and 2.

FIG. 3A shows a cross section through one of the dosing modules 14. Inthis view, the dosing module 14 is positioned over the first powderblend tray 15, ready to begin a first step in the dosing sequence. Thedosing module 14 is comprised of a plurality of dosing nozzles 3 and 4,which have a hollow tube shape. Within each nozzle is a filter 7 whichhave their position within the tube being adjustable so as to set thedesired dose volume of nozzle cavities 3 a and 4 a. Each nozzle isconnected to flow passageways 5 a and 6 a, respectively, which allowvacuum to be drawn via vacuum tubes 23 b and 23, respectively. Thelonger dosing nozzles 4 are mounted to manifold plate 6, and the shorterdosing nozzles 3 are mounted to manifold plate 5. Both manifold plate 5and manifold plate 6 are moveable linearly and are guided, respectively,with bearings 18 and 33 upon shaft 17 and shaft 31, both mounted onsupport 25 which is attached to hub 11. Separating the dosing nozzlesare divider plates 32 which are attached to divider mounting plate 8.

FIG. 3B shows manifold plate 5 and attached dosing nozzles 3 after theyhave moved down in direction A and penetrated into powder blend bed 1.At this point, the vacuum source which is controlled via an externalvalve (not shown) is switched on, pulling a vacuum through vacuum tube23 b. Powder blend volume 1 b from the powder blend bed 1 is sucked intothe nozzle cavity 3 a by negative pressure. Filter 7 prevents suchpowder blend from passing beyond nozzle cavity 3 a. The volume of powderblend volume 1 b, within nozzle cavity 3 a, can be modified byrepositioning filter 7 within dosing nozzle 3. Once dosing is complete,the manifold plate 5 is retracted in direction C to the startingposition as shown in FIG. 4A. A bulb of excess powder blend 1 b thatextends beyond nozzle cavity 3 a is held in place by such negativepressure. The vacant space 1 a left in the powder blend bed 1 as aresult of the removal of powder blend volume 1 b is also shown. Firstpowder blend tray 15 then receives a fresh charge of first powder blendfrom feed hopper 27 (as sown in FIG. 2B). The bed is thus regeneratedafter each fill cycle is complete. Generally this regeneration occurswhile the dosing head assembly 14 (shown in FIG. 4B) indexes to its nextposition.

FIG. 4B is a schematic representation of one of the dosing modules 14moving along direction B from the first powder blend tray 15 to a secondpowder blend tray 16, which in a preferred embodiment contains a powderblend formulation with a different composition (e.g. color and/orpharmaceutically active agent). An example of this could be where thefirst powder blend tray 15 contains a colored formulation containing ananalgesic and the second powder blend tray 16 contains a formulation ofa different color containing a decongestant.

FIG. 4C depicts the removal of excess powder blend volume 1 b fromnozzle 3 while the dosing head assembly 14 moves from its position overpowder blend tray 15 to powder blend tray 16. A scraper bar assembly 40is positioned in the path of the dosing head assembly. As the dosinghead assembly 14 moves horizontally in direction B across the scraperbar assembly 40, the scraper blade 40 a, being maintained at anappropriate height, separates the excess powder blend volume 1 c fromthe powder blend volume 1 b. The leading edge of scraper blade 40 a issharp and the top face of the scraper blade 40 a is maintained flat andparallel to the face of nozzle 3 in order to prevent the excess powderblend volume 1 b from being forcibly pushed into the nozzle cavity 3 a.Excess powder blend volume 1 c is depicted as it falls away from theface of nozzle 3. The excess powder blend is collected in a container(not shown).

FIG. 5A illustrates a dosing module 14 positioned over rotary tablettray 16, ready to begin the filling sequence of dosing nozzles 4 withpowder blend from powder blend bed 2. The dosing nozzles 3 are shownfull of powder blend 1 b from the previous filling step shown in FIG.4A. FIG. 5B shows manifold plate 6 and the dosing nozzles 4 which areattached to it after they have moved down in direction A and penetratedinto powder blend bed 2. The vacuum source which is controlled via anexternal valve (not shown) is switched on and pulls a vacuum throughvacuum tube 23. Powder blend from the powder blend bed 2 is sucked intothe nozzle cavity 4 a by negative pressure. Filter 7 prevents powderblend 2 b from passing beyond nozzle cavity 4 a. In this embodiment, thefill volume for nozzle cavity 4 a is shown to be the same as for nozzlecavity 3 a, however, the volume can be different to produce a tablethaving regions of different volumes such as the tablet illustrated inFIG. 1C. Once dosing of this nozzle cavity 4 a is complete, manifoldplate 6 is retracted in direction C to the starting position as shown inFIG. 6A. The vacant space 2 a left in the powder blend bed 2 by thefilling operation is also shown.

FIG. 6B is a schematic representation of one of the dosing modules 14moving from the second powder blend tray 16 to a position over the dieblock 19. As dosing module 14 moves, a second scraper bar assembly 40separates excess powder blend volume from the powder blend volume 2 b asdiscussed above. Die block 19 is mounted with dial plate 22 which ispart of the rotary table assembly 204 (as shown in FIG. 2B). The dialplate 22 is synchronized with the dosing head assembly 13 (as shown inFIG. 2B) such that after an indexing motion, dosing module 14 ispositioned over the forming cavity 19 a, as shown in cross section inFIG. 7A. Each forming cavity 19 a has an inner wall 31, and a secondopening 33 (for forming tool 20 to enter the forming cavity 19 a) and afirst opening 34 (for upper forming tool 321 as shown in FIG. 10 toenter the forming cavity 19 a). As shown in this illustration, nozzlecavities 3 a and 4 a (shown empty in FIG. 3A) are now filled with powderblend volumes 1 b and 2 b, respectively. Lower forming tools 20 havebeen inserted through second openings 33 in the bottom of die block 19.Forming tools 20 are housed in lower tool holder block 10. FIG. 7B showsa three dimensional view of a portion of the die block 19, forming tool20, and a portion of the dosing nozzles 3 and 4 which are separated bydivider plate 32.

As shown in FIG. 7C, the first step in the sequence of filling theforming cavity 19 a entails the insertion of divider plate 32 into theforming cavity 19 a. This is accomplished by moving divider mountingplate 8 in direction A down such that movable divider 32 is locatedwithin the forming cavity 19 a. As shown in the illustration, movabledivider 32 creates a barrier within the forming cavity 19 a, therebyseparating forming cavity 19 a it into two die chambers, namely dieblock chambers 19 b and 19 c. The movable dividers 32 are constructed ofany suitable rigid material such as stainless steel, Delrin®, nylon, orTeflon®. The movable divider has a geometry that contours to the diecavity and lower form tool (e.g., a width that is slightly smaller thanthe diameter of the die cavity to allow for easy insertion andextraction, such as a clearance of between 0.002 inches to 0.062inches).

FIG. 8A illustrates the filling sequence of the operation. In thissequence, dosing nozzles 3 and 4 are shown evacuated, with the powderblend 1 b and 2 b now residing on either side of the movable divider 32,respectively within die block chambers 19 b and 19 c (as previouslyshown empty in FIG. 7C). To achieve the full and complete discharge ofthe powder blend from the nozzles, an external valve switches from avacuum source to a pressure source, sending positive air pressurethrough vacuum tubes 23 and 23 b. This positive air pressure passesthrough filters 7 and blows the powder blend volumes 1 b and 2 b intothe die block chambers 19 b and 19 c, respectively. The air pressurealso serves to purge filter 7 of small particulates so that they areready to repeat the next dosing sequence. After the purge step, themovable divider 32 is withdrawn from the forming cavity 19 a by movingdivider mounting plate 8 upward in direction C to its home position asshown in FIG. 8B. As shown in FIG. 8B, the movable dividers have createda interface line between powder blend volumes 1 b and 2 b during thefilling operation.

The fact that two powdered formulations are deposited at one time is amajor distinguishing feature of this invention over the existingsequential layer upon layer compression method, and it offerssignificant advantages. The fact that both components are dosed at onetime greatly simplifies the manufacturing apparatus, and it can offer ahigher tablet output from a given amount of equipment tooling.

In the above embodiment of the invention, a process of vacuum fillingthe nozzles is utilized. This filling method is advantageous in that itallows for very accurate filling of poorly flowing powder formulations.Poorly flowing and/or highly porous formulations are often required formanufacturing orally disintegrating tablets. These tablets often have avery soft, erodible construct to assist disintegration in the mouth. Fortablet forms that do not require these attributes and/or that areconstructed from more dense and compacted formulations, the vacuumfilling method can optionally be replaced by merely tamping the powderblend beds. In such an embodiment, the vacuum source and filters areeliminated. The dose tubes are inserted into the powder blend bed, andthe force of insertion and subsequent compaction make the powder blendstick to the inside of the nozzle cavity by the force of friction. Insuch an embodiment, ejector pins (not shown) may be substituted for thefilters, residing in the same location with the dosing nozzles 3 and 4to control volume of powder blend within each dosing nozzle. Suchejector pins may be attached to a plate that moves the ejector pins downat the appropriate time to evacuate the powder blend from the nozzlecavities.

FIG. 9 depicts the die block 19 now filled with powder blend rotating inan indexing fashion over to the forming station 202 in direction B. FIG.10 depicts a cross section through the forming station 202. Formingstation 202 is comprised of a press frame 339, moving platen 343, movingplaten 342, power cylinder 345, power cylinder 344, and upper formingtools 321 housed in upper tool holder 311. In one embodiment, the powderblend volumes 1 b and 2 b are shaped together by using power cylinders345 and 344 to apply a force to forming tools 20 and 321. As the formtools move closer together (upper forming tools 321 moves in direction Aand lower forming tools 20 moves in direction C), the powder blendvolumes 1 b and 2 b are shaped in the form of the tablet 350 as shown inFIG. 11.

In one embodiment, radio frequency energy is used to add heat energy tothe powder blends 1 b and 2 b to create a sintered tablet 350. In suchan embodiment, RF generator 12 is depicted symbolically in FIG. 9 andFIG. 10. In one embodiment, the configuration of the RF generator 12 isa free running oscillator system. Such as system is typically composedof a power vacuum tube (such as a triode) and a DC voltage source (e.g.,between 1000 and 8000 volts) connected across the cathode and plate(anode). A tank circuit is often used to impose a sinusoidal signal uponthe control grid and electrodes, thereby producing the necessaryfrequency (typically 13.56 MHZ or 27.12 MHZ) and high voltage field. Anexample of such RF generator is the COSMOS Model C10X16G4 (CosmosElectronic Machine Corporation, Farmingdale, N.Y.). In anotherembodiment, RF energy can be provided by a 50 Ohm system composed of awaveform generator which feeds a radio frequency signal to poweramplifiers which are coupled to the electrodes and the load by animpedance matching network.

In FIG. 10, movable electrode plate 340 and movable electrode plate 341are shown mounted, respectively, to moving platens 342 and 343. Thepress is represented in its open position in FIG. 10. Linear movement ofmoving platens 343 and 342 and their respective attached movableelectrode plates 341 and 340 is respectively generated by powercylinders 345 and 344, which can be a device such as air cylinders orservo motor. Moving platens 343 and 342 are electrically isolated frommovable electrode plates 341 and 340, respectively. RF generator 12 isconnected to the movable electrode plates 341 and 340 respectivelythrough wires 380 and 381. A movable electrode assembly 390, movable indirection A, is shown in its up position, and movable electrode assembly370, movable in direction C, is shown in its down position. Upperforming tools 321 and retainer plate 311 are attached to the movableelectrode plate 341 and, consequently, move up and down with it. Powderblend volumes 1 b and 2 b are within die block 19.

FIG. 11 is a section view through the same RF station, but shows themovable electrode plates 341 and 340 in a closed position (having movedin directions A and C, respectively). pressing forming tools 321 and 20towards each other to both shape and apply RF energy to powder blendvolumes 1 b and 2 b. This RF energy heats powder blend volumes 1 b and 2b to create a solid tablet 350. After the RF forming cycle is complete,the movable electrode assemblies 390 and 370 move back to their startingpositions.

In an alternate embodiment illustrated in FIG. 12A, the forming toolscan be constructed to achieve localized heating effects and can also beconfigured to shape the electric field that is developed across thetools. An RF generator 12 is connected to movable electrode plates 460and 461. Forming tools 421 and 420 are constructed of an electricallyconductive material, and they respectively have an attachment 440 and430 which are made of electrical and RF energy insulative material (suchas ceramic, Teflon®, polyethylene, or high density polyethylene). Dieblock 19 is also constructed of electrical and RF energy insulativematerial. This configuration creates regions on the forming tool wherethere is greater distance between the conductive portions of the formingtools 421 and 420 to weaken the electric field. This geometry willproduce a tablet with lesser heating of the powder blend in area 410since the electric field is weaker due to the greater distance betweenthe conductive portions of forming tools 421 and 420. Area 400 of thepowder blend receives the greater heating effect since the conductiveportion of forming tools 421 and 420 are closer together, thereby makingthe electric field between them greater. This configuration allows atablet to be formed with regions of different harnesses and/or textures.

Once the tablets have been formed, the final step in the manufacturingprocess is to eject the tablets from the die block 19 using tabletejection station 203. FIG. 12B shows the die block 19 with formedtablets 350 after they have indexed into the tablet ejection station203. Ejector pins 500 move down in direction A to eject finished tablets350 out of die block 19 into a package container 501 (e.g., a blisterpackage) as shown in FIG. 12C. This direct placement of tablets into thepackage helps prevent breakage that could occur while using typicalmeans such as feeders or by dumping tablets into transport drums.

Interface Between Regions of Tablet

In FIG. 7B, the divider plate 32 in this embodiment has a straight,linear geometry and is positioned at the center of the cylindricalvolume of the forming cavity 19 a. In this configuration, a tablet, suchas tablet 100 as shown in FIG. 1A, can be produced from themanufacturing operation, wherein the interface 103 between the firstregion 101 and second region 102 is along the diameter of the major faceof the tablet. The divider plate, however, can have other geometriesthat are non-linear, such as angled, curved, or wave shaped. A tabletproduced by wave shape divider plate is shown in FIG. 1B. The wave shapethus forms the curvilinear interface 114 between first region 112 andsecond region 113. FIG. 13A is an illustration of the wavy divider plate600 that can be used to produce a tablet similar to the tablet of FIG.1B. FIG. 13B depicts an arc-shaped divider plate 610 which can used toproduce a tablet similar to the tablet of FIG. 1C having a curvedinterface 115.

The divider plate functions to create a barrier between the powderblends during the filling operation. By preventing the intermingling ofthe two powder blends, a crisp interface is created. In one embodiment,a more blended interface may be desired, as depicted in FIG. 1D. Tocreate the blended interface 119 depicted in the tablet on FIG. 1D, inone embodiment, a divider plate is not used. As such, when the dosingnozzles simultaneously deposit the powder blend together without adivider plate, the two powder blends intermingle within the die cavity.Since air pressure may be used in one embodiment of the dosing nozzleoperation to blow the powder blend into the die cavity, the nozzle canalso be configured to obtain swirling or turbulence effects to enhanceintermingling of the regions. FIG. 13C depicts a further designvariation where a divider plate 620 is used in the manufacturingsequence. It has been divided into segments where openings exist thatcreate a tablet with staggered regions of crisp and blended interfaces.In this case, the resulting tablet would havecrisp-blended-crisp-blended-crisp interface region between the twoindividual components.

To produce the bull's eye tablet geometry that is illustrated in FIG.1E, the dosing nozzle configuration as shown in FIG. 14A can be used. Asshown in isometric view FIG. 14A, the dosing nozzles are comprised ofconcentric telescoping tubes. FIG. 14B is a section through theconcentric dosing nozzles. In this embodiment, an outer dosing nozzle630 is comprised of an outer tube 630 a and an inner tube 630 b and ismovable and independent of inner dosing nozzle 631 which is alsoindependently movable. In this embodiment, as shown in FIG. 14B-14D, theouter dosing nozzle 630 is movable in directions A and C to obtainpowder blend volume 1 b from powder blend bed 1 within first powderblend tray 15, leaving vacant space 1 a. As shown in FIGS. 14E-14G,inner dosing nozzle 631 is also movable in directions A and C to obtainpowder blend 2 b from powder blend bed 2 within first powder blend tray16, leaving vacant space 2 a. The amount of powder blend volumes 1 b and2 b is dependent upon the placement of filters 637. As shown in FIGS.14H-14J, both inner nozzle 631 and outer nozzle 630 are movable indirections A and C in order to deposit powder blend volumes 1 b and 2 bsimultaneously into a die cavity 19 a within die block 19 to achieve thedesired bull's eye powder blend distribution.

In one embodiment, a lubricant is added to forming cavity prior to theaddition of the flowable powder blend blend. This lubricant may be aliquid or solid. Suitable lubricants include, but are not limited to;solid lubricants such as magnesium stearate, starch, calcium stearate,aluminum stearate and stearic acid; or liquid lubricants such as but notlimited to simethicone, lecithin, vegetable oil, olive oil, or mineraloil. In certain embodiments, the lubricant is added at a percentage byweight of the tablet of less than 5 percent, e.g. less than 2 percent,e.g. less than 0.5 percent. In certain embodiments, the presence of ahydrophobic lubricant can disadvantageously compromise thedisintegration or dissolution properties of a tablet. In one embodimentthe tablet is substantially free of a hydrophobic lubricant. Examples ofhydrophobic lubricants include magnesium stearate, calcium stearate andaluminum stearate.

Manufacturing Method for Single Region Tablets

In one aspect, the present invention features a machine capable ofproducing single region tablet. One embodiment of such a single-regiontablet machine 1500 is depicted in FIGS. 15A and 15B, which is similarto the multi-region tablet machine 200 depicted above in FIGS. 2A and2B. FIG. 15A illustrates a plan view of this embodiment, and FIG. 15Billustrates a three dimensional view of this embodiment. The machine ofFIG. 15A and FIG. 15B differs from that of FIG. 2A and FIG. 2B in thatthe powder blend dosing station 701 is designed to accurately dose onlya single powder blend. In a preferred embodiment, the dosing headassembly 701 is comprised of two identical dosing modules 714 arrayedradially from a central hub 711. In this embodiment, the rotary dosehead assembly sequentially indexes first over powder blend bed 1 toobtain a volume of powder blend from powder blend bed 1.

FIG. 16A shows a cross section through one of the dosing modules 714. Inthis view, the dosing module 714 is positioned over the first powderblend tray 15, ready to begin a first step in the dosing sequence. Thedosing module 714 is comprised of a plurality of dosing nozzles 703,which have a hollow tube shape. Within each nozzle is a filter 707 whichhave their position within the tube being adjustable so as to set thedesired dose volume of nozzle cavities 703 a. Each nozzle is connectedto flow passageways 706 a, which allow vacuum to be drawn via vacuumtube 723. The dosing nozzles 703 are mounted to manifold plate 706,which is moveable linearly and are guided with bearings 718 upon shaft717 and shaft 731.

FIG. 16B shows manifold plate 706 and attached dosing nozzles 703 afterthey have moved down in direction A and penetrated into powder blend bed1. At this point the vacuum source which is controlled via an externalvalve (not shown), is switched on, pulling a vacuum through vacuum tube723. Powder blend from the powder blend bed 1 is sucked into the nozzlecavity 703 a. Filter 707 prevents such powder blend from passing beyondnozzle cavity 703 a. The volume of powder blend within nozzle cavity 703a can be modified by repositioning filter 707 within dosing nozzle 703.Once dosing is complete, the manifold plate 706 is retracted indirection C to the starting position as shown in FIG. 17A. The vacantspace 1 a left in the powder blend bed 1 as a result of the fillingoperation is also shown. As shown in FIG. 17A, nozzle cavity 703 a isnow filled with powder blend volume 701 b.

FIG. 17B is a schematic representation of one of the dosing modules 714moving from the first powder tray 15 to a position over the die block19. Die block 19 is mounted with dial plate 22 which is part of therotary table assembly 204. The dial plate 22 is synchronized with thedosing head assembly 701 (as shown in FIG. 15B) such that after anindexing motion, dosing module 714 is positioned over the forming cavity19 a, as shown in cross section in FIG. 18A. As shown in thisillustration, nozzle cavities 703 a (shown empty in FIG. 16A) are nowfilled with powder volume 701 b. Lower forming tools 20 are theninserted through the bottom of die block 19. Forming tools 20 are housedin tool holder block 10.

FIG. 18B illustrates the filling sequence of the operation. Here dosingnozzles 3 are shown evacuated with the powder blend volume 701 b nowresiding within die block 19. To achieve the full and complete dischargeof the powder blend from the nozzles, an external valve switches from avacuum source to a pressure source, sending air pressure through vacuumtube 723. This air pressure passes through filters 707 and blows thepowder blend volume 701 b into the die block 19.

FIGS. 19-20 depicts the die block 19, now filled with powder blend,rotating in an indexing fashion over to the forming station 202(discussed above). As the forming tools move closer together alongdirections A and C, the powder blend volumes 1 b are shaped to the formof the tablet 750 (as shown in FIG. 21).

Once the tablets have been formed, the final step in the manufacturingprocess is to eject the tablets from the die block 19 using tabletejection station 203 (discussed above). FIG. 22A shows the die block 19with formed tablets 750 after they have indexed into the tablet ejectionstation 203. Ejector pins 500 move down in direction A to eject finishedtablets 750 out of die block 19 into a package container 501 (e.g., ablister package) as shown in FIG. 22. This direct placement of tabletsinto the package helps prevent breakage that could occur while usingtypical means such as feeders or by dumping tablets into transportdrums.

Radiofrequency Heating of Tablet Shape to Form Tablet

In one embodiment, Radiofrequency heating is utilized in the manufactureof the tablets. Radiofrequency heating generally refers to heating withelectromagnetic field at frequencies from about 1 MHz to about 100 MHz.In one embodiment of the present invention, the RF-energy is within therange of frequencies from about 1 MHz to about 100 MHz (e.g., from about5 MHz to 50 MHz, such as from about 10 MHz to about 30 MHz). TheRF-energy is used to impart energy (e.g., to heat) the powder blend(s).The degree of any compaction to the powder blend, the type and amount ofmaterials within the powder blend, and the amount of RF energy used candetermine the hardness and/or type of tablet, such as whether an oraldisintegrating tablet, a soft chewable tablet is manufactured, a gum, ora lozenge is manufactured.

RF energy generators are well known in the art. Examples of suitable RFgenerators include, but are not limited to, COSMOS Model C10X16G4(Cosmos Electronic Machine Corporation, Farmingdale, N.Y.).

In one embodiment, the upper and lower forming tools serve as theelectrodes (e.g., they are operably associated with the RF energysource) through which the RF energy is delivered to the tablet shape. Inone embodiment, there is direct contact between at least one RFelectrode (e.g., forming tool) and the tablet shape. In anotherembodiment, there is no contact between any of the RF electrode (e.g.,forming tools) and the tablet shape. In one embodiment, the RFelectrodes are in direct contact with the surface of the tablet shapewhen the RF energy is added. In another embodiment, the RF electrodesare not in contact (e.g., from about 1 mm to about 1 cm from the surfaceof the tablet shape) during the addition of the RF energy.

In one embodiment, the RF energy is delivered while the tablet shape isbeing formed. In one embodiment, the RF energy is delivered once thetablet shape is formed. In one embodiment, the RF energy is deliveredafter the tablet shape has been removed from the die.

In one embodiment, the RF energy is applied for a sufficient time tobind substantially all (e.g., at least 90%, such as at least 95%, suchas all) of the powder blend the tablet shape. In one embodiment, the RFenergy is applied for a sufficient time to bind only a portion (e.g.,less than 75%, such as less than 50%, such as less than 25%) of thepowder blend within the tablet shape, for example only on a portion ofthe tablet shape, such as the outside of the tablet shape.

In alternate embodiment of the invention, the forming tools can beconstructed to achieve localized heating effects and can also beconfigured to shape the electric field that is developed across theforming tools. Examples of such forming tools are depicted in FIGS.11-14 of US Patent Application No. 2011/0068511.

In one embodiment, to help reduce sticking, the tablet is cooled withinthe forming cavity to cool and/or solidify the tablet. The cooling canbe passive cooling (e.g., at room temperature) or active cooling (e.g.,coolant recirculation cooling). When coolant recirculation cooling isused, the coolant can optionally circulate through channels inside theforming tools (e.g., punches or punch platen) and/or die or die block.In one embodiment, the process uses a die block having multiple diecavities and upper and lower punch platens having multiple upper andlower punched for simultaneous forming of a plurality of tablets whereinthe platens are actively cooled.

In one embodiment, there is a single powder blend forming the tabletshape which is then heated with the RF energy. In another embodiment,the tablet is formed of at least two different powder blends, at leastone powder blend being RF-curable and at least one formulation being notRF-curable. When cured with RF energy, such tablet shape develops two ormore dissimilarly cured zones. In one embodiment, the outside area ofthe tablet shape is cured, while the middle of the tablet shape is notcured. By adjusting the focus of the RF heating and shape of the RFelectrodes, the heat delivered to the tablet shape can be focused tocreate customized softer or harder areas on the finished tablet.

In one embodiment the RF energy is combined with a second source of heatincluding but not limited to infrared, induction, or convection heating.In one embodiment, the addition of the second source of heat isparticularly useful with a secondary non-RF-meltable binder present inthe powder blend.

Microwave Heating of Tablet Shape to Form Tablet

In one embodiment, microwave energy is used in place of radiofrequencyenergy to manufacture the dosage form (e.g., tablet). Microwave heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 100 MHz to about 300 GHz. In one embodiment of the presentinvention, the microwave energy is within the range of frequencies fromabout 500 MHz to about 100 GHz (e.g., from about 1 GHz to 50 GHz, suchas from about 1 GHz to about 10 GHz). The microwave energy is used toheat the powder blend. In such an embodiment, a microwave energy sourceand microwave electrodes are used in the machine used to manufacture thedosage form.

Inserts within Tablet Shape

In one embodiment, an insert is incorporated into the tablet shapebefore the RF energy is delivered. Examples include solid compressedforms or beads filled with a liquid composition. Such incorporation ofan insert is depicted in FIGS. 3A-3G.

In one embodiment the pharmaceutically active agent is in the form of agel bead, which is liquid filled or semi-solid filled. The gel bead(s)are added as a portion of the powder blend. In one embodiment, thetablet of this invention has the added advantage of not using a strongcompaction step, allowing for the use of liquid or semisolid filledparticles or beads which are deformable since they will not rupturefollowing the reduced pressure compaction step. These bead walls maycontain gelling substances such as: gelatin; gellan gum; xanthan gum;agar; locust bean gum; carrageenan; polymers or polysaccharides such asbut not limited to sodium alginate, calcium alginate, hypromellose,hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches.The bead walls may further contain a plasticizer such as glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate andtributyl citrate. The pharmaceutically active agent may be dissolved,suspended or dispersed in a filler material such as but not limited tohigh fructose corn syrup, sugars, glycerin, polyethylene glycol,propylene glycol, or oils such as but not limited to vegetable oil,olive oil, or mineral oil.

In one embodiment, the insert is substantially free of RF-absorbingingredients, in which case application of the RF energy results in nosignificant heating of the insert itself In other embodiments, theinsert contains ingredients and are heated upon exposure to RF energyand, thus, such inserts can be used to heat the powder blend.

Effervescent Couple

In one embodiment, the powder blend further contains one or moreeffervescent couples. In one embodiment, effervescent couple containsone member from the group consisting of sodium bicarbonate, potassiumbicarbonate, calcium carbonate, magnesium carbonate, and sodiumcarbonate, and one member selected from the group consisting of citricacid, malic acid, fumaric acid, tartaric acid, phosphoric acid, andalginic acid.

In one embodiment, the combined amount of the effervescent couple(s) inthe powder blend/tablet is from about 2 to about 20 percent by weight,such as from about 2 to about 10 percent by weight of the total weightof the powder blend/tablet.

Orally Disintegrating Tablet

In one embodiment, the tablet is designed to disintegrate in the mouthwhen placed on the tongue in less than about 60 seconds, e.g. less thanabout 45 seconds, e.g. less than about 30 seconds, e.g. less than about15 seconds.

In one embodiment, the tablet meets the criteria for OrallyDisintegrating Tablets (ODTs) as defined by the draft Food and DrugAdministration guidance, as published in April, 2007. In one embodiment,the tablet meets a two-fold definition for orally disintegrating tabletsincluding the following criteria: 1) that the solid tablet is one whichcontains medicinal substances and which disintegrates rapidly, usuallywithin a matter of seconds, when placed upon the tongue and 2) beconsidered a solid oral preparation that disintegrates rapidly in theoral cavity, with an in vitro disintegration time of approximately 30seconds or less, when based on the United States Pharmacopeia (USP)disintegration test method for the specific medicinal substance orsubstances.

Tablets Coatings

In one embodiment, the tablet includes an additional outer coating(e.g., a translucent coating such as a clear coating) to help limit thefriability of the tablet. Suitable materials for translucent coatingsinclude, but are not limited to, hypromellose, hydroxypropylcellulose,starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol andpolyethylene glycol mixtures and copolymers, and mixtures thereof.Tablets of the present invention may include a coating from about 0.05to about 10 percent, or about 0.1 to about 3 percent by weight of thetotal tablet.

Hardness/Density of Tablet

In one embodiment, the tablet is prepared such that the tablet isrelatively soft (e.g., capable of disintegrating in the mouth or beingchewed). In one embodiment, the hardness of the tablet of the presentinvention uses a Texture Analyzer TA-XT2i to measure the peakpenetration resistance of the tablet. The texture analyzer is fittedwith a flat faced cylindrical probe having a length equal to or longerthan the thickness of the tablet (e.g., 7 mm) and a diameter of 0.5 mm.Tablet hardness is determined by the maximum penetration force of aprobe boring through the center of a major face of the tablet or thecenter of the region on the major face when the major face has more thanone region, where the probe is a 0.5-mm diameter, stainless steel,cylindrical wire with a blunt end and the tablet is supported by a solidsurface having a 2-mm diameter through-hole centered in a counter borehaving a diameter slightly greater than that of the tablet, for example0.51 inches for a 0.5 inch diameter tablet. The probe, tablet,counter-bore, and 2-mm through hole are all concentric to one another.The texture analyzer is employed to measure and report the force ingrams as the probe moves at 0.1 millimeters per second through thetablet, until the probe passes through at least 80% of the thickness ofthe tablet. The maximum force required to penetrate the tablet isreferred to herein as the peak resistance to penetration (“peakpenetration resistance”).

In one embodiment, the peak penetration resistance at the center of amajor face is from about 2 grams to about 500 grams, such as from about50 grams to about 600 grams, such as from about 100 grams to about 300grams. In one embodiment, one region of the tablet has a peakpenetration resistance that is greater than the peak penetrationresistance of the other region of the tablet (e.g., at least 10%greater, such as at least 25% greater, such as at least 50% greater,such as at least 100% greater).

In one embodiment, the density of the tablet is less than about 0.8g/cc, such as less than about 0.7 g/cc. In one embodiment, one region ofthe tablet has a density that is greater than the density of the otherregion of the tablet (e.g., at least 5% greater, such as at least 10%greater, such as at least 25% greater, such as at least 50% greater).

In one embodiment, the tablets have a friability of less than 10percent, such as less than 5 percent, such as less than 1 percent. Asused herein, “friability” is measured using the USP 24 NF 29 TabletFriability (Section 1216) with the modification of using 3 tablets for10 rotations (unless otherwise noted) rather than 10 tablets for 100rotations.

Use of Tablet

The tablets may be used as swallowable, chewable, or orallydisintegrating tablets to administer the pharmaceutically active agent.

In one embodiment, the present invention features a method of treatingan ailment, the method including orally administering theabove-described tablet wherein the tablet includes an amount of thepharmaceutically active agent effective to treat the ailment. Examplesof such ailments include, but are not limited to, pain (such asheadaches, migraines, sore throat, cramps, back aches and muscle aches),fever, inflammation, upper respiratory disorders (such as cough andcongestion), infections (such as bacterial and viral infections),depression, diabetes, obesity, cardiovascular disorders (such as highcholesterol, triglycerides, and blood pressure), gastrointestinaldisorders (such as nausea, diarrhea, irritable bowel syndrome and gas),sleep disorders, osteoporosis, and nicotine dependence.

In one embodiment, the method is for the treatment of an upperrespiratory disorder, wherein the pharmaceutically active agent isselected from the group of phenylephrine, cetirizine, loratadine,fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine,chlophedianol, and pseudoephedrine.

In this embodiment, the “unit dose” is typically accompanied by dosingdirections, which instruct the patient to take an amount of thepharmaceutically active agent that may be a multiple of the unit dosedepending on, e.g., the age or weight of the patient. Typically the unitdose volume will contain an amount of pharmaceutically active agent thatis therapeutically effective for the smallest patient. For example,suitable unit dose volumes may include one tablet.

EXAMPLES

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples.

Example 1 Manufacture of Red Powder Blend Containing Loratadine

The loratadine powder blend for an orally disintegrating tablet,containing the ingredients of Table 1, is manufactured as follows:

TABLE 1 Loratadine Powder Blend Formulation Ingredient G/Batch mg/Tablet% per tablet Erythritol¹ 61.47 129.50 61.47 Loratadine 4.75 10.0 4.75Maltodextrin² 33.23 70.00 33.23 Red Colorant 0.04 0.075 0.04 SucraloseUSP 0.14 0.3 0.14 Mint Flavor³ 0.38 0.8 0.38 Total 100.0 210.68 100.0¹Commercially available from Corn Products in Westchester, IL as Erysta3656 DC (80% erythritol) ²Commercially available from National Starch inBridgewater, NJ ³Commercially available from International Flavors andFragrances in New York, NY

First, the sucralose, colorant, and flavor were placed together into a500 cc sealable plastic bottle. The mixture was then blendedend-over-end manually for approximately 2 minutes. The resultingmixture, the erythritol, loratadine, and the maltodextrin were thenadded to another 500 cc sealable plastic bottle and mixed end-over-endmanually for approximately 5 minutes.

Example 2 Manufacture of White Powder Blend Containing Acetaminophen

The acetaminophen powder blend for a bisected orally disintegratingtablet, containing the ingredients of Table 2, was manufactured asfollows. The sucralose, and flavor from the formula in Table 2 werepassed through a 20 mesh screen. The sieved materials were placed into a500 cc plastic bottle and blended end over end with the maltodextrin,erythritol and encapsulated acetaminophen in Table 2.

TABLE 2 Acetaminophen Powder Blend Formulation Ingredient G/Batchmg/Tablet % per tablet Erythritol¹ 44.72 129.50 44.72 EncapsulatedAcetaminophen 30.73 89.01 30.73 Maltodextrin² 24.17 70.00 24.17Sucralose USP 0.10 0.3 0.10 Mint Flavor³ 0.28 0.8 0.28 Total 100.0289.69 100.0 ¹Commercially available from Corn Products in Westchester,IL as Erysta 3656 DC (80% erythritol) ²Commercially available fromNational Starch in Bridgewater, NJ ³Commercially available fromInternational Flavors and Fragrances in New York, NY

Example 3 Preparation of Bi-Sected Orally Disintegrating Tablet

A bi-sected orally disintegrating tablet having loratadine in onehalf-section and acetaminophen in the other half-section aremanufactured as follows. 210.68 mg of the powder blend containingloratidine from Table 1 is dosed into a forming cavity. 289.69 mg of thepowder blend containing acetaminophen from Table 2 is then dosed intothe forming cavity using a physical separator to while dosing to preventmixing into the loratidine blend. The tablet is then tamped to create a625.65 mg tablet. The cavity is then activated with RF energy asdescribed in Example 2 for approximately 2 to 5 seconds to form theorally disintegrating tablet and subsequently removed from the dieblock.

Example 4 Preparation of Bi-Sected Placebo Orally Disintegrating Tablet(ODT)

TABLE 3 Region 1 of Bi-Sected Placebo ODT mg/tab Material G/Batch regionWeight % Dextrose Monohydrate, Fine powder 64.54 129.08 64.54 Sucralose0.15 0.30 0.15 Vanilla Flavor¹ 0.40 0.80 0.40 Maltodextrin² 34.89 69.7834.89 Blue #1 Al Lake Colorant 0.02 0.04 0.02 TOTAL 100.0 200.00 100.0¹Commercially available from the International Flavors and FragrancesCorporation in Hazlet, NJ ²Commercially available from National Starchin Bridgewater, NJ

TABLE 4 Region 1 of Bi-Sected Placebo ODT mg/tab Material G/Batch regionWeight % Dextrose Monohydrate, Fine powder 64.54 129.08 64.54 Sucralose0.15 0.30 0.15 Mint Flavor¹ 0.40 0.80 0.40 Maltodextrin² 34.89 69.7834.89 Green Lake Colorant 0.02 0.04 0.02 TOTAL 100.0 200.00 100.0¹Commercially available from the International Flavors and FragrancesCorporation in Hazlet, NJ ²Commercially available from National Starchin Bridgewater, NJA bi-sected orally disintegrating placebo tablet having vanilla flavorand blue colorant in one region and green colorant and mint region inthe other region is manufactured as follows. 200.0 mg of the powderblend from Table 3 is placed into the forming cavity. A physicalseparator is then placed within the die while dosing the second portionto prevent mixing into the first blend. 200.0 mg of the powder blendfrom Table 4 is then added into the forming cavity and tamped. Thecavity is then activated with RF energy as described in Example 2 forapproximately 2 to 5 seconds to form the orally disintegrating tablet at400.0 mg and subsequently removed from the die block.

Example 5 Preparation of Bi-Sected Orally Disintegrating Tablet Via aLyophillization Process Containing Loratidine and Phenylephrine

A bi-sected orally disintegrating tablet having loratadine in one regionand phenylephrine in the other region is manufactured as follows via alyophillization process. Using the formula in Table 5, a solution isprepared while mixing in a suitable vessel. The gelatin, mannitol,flavorants, sucralose and colorant are added while mixing atapproximately 50 RPM. After the gelatin is dissolved the loratidine isadded and mixed. The resulting mixture is then deposited into a die in161.07 portions. The contains a partition across the lateral section ofthe die to allow for deposition of the second portion. The firstloratidine portion is dried and frozen and the partition is removed fromthe die. The second solution including phenylephrine is preparedutilizing the formula in Table 2 and the same mixing parameters as theloratidine solution. The phenyleprine solution is then added to the diecontaining the loratidine portion. The form is then dried and frozen,resulting in a bisected orally disintegrating tablet includingloratadine in one portion and phenylephrine in a second portion.

TABLE 5 Region 1 of Bi-Sected Placebo ODT via Lyophillization mg/tabMaterial G/Batch region Weight % Mannitol 54.0 6.00 27.00 Gelatin 54.06.00 27.00 Peppermint Flavor¹ 1.78 0.20 0.89 Vanilla Flavor¹ 0.44 0.050.22 Loratidine 88.00 10.00 44.00 Sucralose 1.78 0.20 0.89 Blue #1 AlLake Colorant 0.09 0.01 0.04 Purified Water 1228.57 a N/A TOTAL 142922.55 100.0 a - purified water removed upon drying ¹Commerciallyavailable from the International Flavors and Fragrances Corporation inHazlet, NJ

TABLE 6 Region 2 of Bi-region ODT via Lyophillization mg/tab MaterialG/Batch region Weight % Mannitol 60.0 6.00 30.00 Gelatin 60.0 6.00 30.00Peppermint Flavor¹ 2.00 0.20 1.00 Vanilla Flavor¹ 0.50 0.05 0.25Phenylephrine HCl 75.16 7.50 37.58 Sucralose 2.00 0.20 1.00 Blue #1 AlLake Colorant 0.060 0.01 0.0005 Purified Water 1228.57 a N/A TOTAL 142819.96 100.0 a - purified water removed upon drying ¹Commerciallyavailable from the International Flavors and Fragrances Corporation inHazlet, NJ

Example 6 Preparation of Bi-Sected Placebo Orally Disintegrating Tabletvia a Lyophillization Process

A bi-sected placebo orally disintegrating tablet having is manufacturedas follows via a lyophillization process. Using the formula in Table 7,a solution is prepared while mixing in a suitable vessel. The gelatin,mannitol, flavorants, sucralose and colorant are added while mixing atapproximately 50 RPM. The resulting mixture is then deposited into a diein 161.07 portions. The contains a partition across the lateral sectionof the die to allow for deposition of the second portion. The firstportion is dried and frozen and the partition is removed from the die.The second solution e is prepared utilizing the formula in Table 8 andthe same mixing parameters as the first solution. 142.57 mg portions ofthe phenyleprine solution is then added to the die already containingthe loratidine portion. The form is then dried and frozen, resulting ina bisected orally disintegrating tablet including blue colorant in oneportion and no colorant in a second portion.

TABLE 7 Region 1 of Bi-Sected Placebo ODT via Lyophillization with BlueColorant mg/tab Material G/Batch region Weight % Mannitol 96.0 7.0048.01 Gelatin 96.0 7.00 48.01 Peppermint Flavor¹ 3.42 0.25 1.71 VanillaFlavor¹ 0.82 0.06 0.41 Sucralose 3.42 0.25 1.71 Blue #1 Al Lake Colorant0.28 0.02 0.14 Purified Water 1228.14 a N/A TOTAL 1428 14.58 100.0 a -purified water removed upon drying ¹Commercially available from theInternational Flavors and Fragrances Corporation in Hazlet, NJ

TABLE 8 Region 2 of Bi-Sected Placebo ODT via Lyophillization withoutColorant mg/tab Material G/Batch region Weight % Mannitol 96.0 7.0048.00 Gelatin 96.0 7.00 48.00 Peppermint Flavor¹ 3.44 0.25 1.72 VanillaFlavor¹ 0.82 0.06 0.41 Sucralose 3.44 0.25 1.72 Purified Water 1228.57 aN/A TOTAL 1428 14.56 100.0 a - purified water removed upon drying¹Commercially available from the International Flavors and FragrancesCorporation in Hazlet, NJ

It is understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

What is claimed is:
 1. A machine for the production of a solid dosageform, said machine comprising: (a) a die block having one or moreforming cavities each having an inner wall, a first opening at thesurface of one side of said die block, and a second opening at thesurface on the opposite side of said die block; (b) one or more firstdosing nozzle adapted to both measure an amount of a first powder blendand discharge said measured amount of said first powder blend within oneof said one or more forming cavity; (d) one or more first forming toolseach adapted to move into one of said cavities through the first openingof said forming cavity; (e) one or more second forming tools eachadapted to move adjacent to one of said second openings or into one ofsaid cavities through the second opening of said forming cavity; (f) atleast one first RF electrode operably associated with said one or morefirst forming tools, said one or more second forming tools, or saidinner wall of said one or more forming cavities; and (g) at least onesecond RF electrode operably associated with said one or more firstforming tools, said one or more second forming tools, or said inner wallof said one or more forming cavities; wherein said machine is adapted toform a dosage form between a first forming tool and a second formingtool within a forming cavity and wherein said first RF electrode andsaid second RF electrode are arranged within said machine such that whenRF energy is applied between said first RF electrode and said second RFelectrode, said RF energy passes through the portion of said formingcavity adapted to form said dosage form.
 2. A machine of claim 1,wherein said one or more first dosing nozzles are adapted to measure anamount of said first powder blend using negative pressure.
 3. A machineof claim 1, wherein said one or more first dosing nozzles are adapted todischarge said measured amount of said first powder blend positivepressure.
 4. A machine of claim 2, wherein said one or more first dosingnozzles are adapted to discharge said measured amount of said firstpowder blend positive pressure.
 5. A machine if claim 1, wherein saidmachine further comprises an RF energy source in communication with saidfirst RF electrode and said second RF electrode.
 6. A machine of claim1, wherein said first RF electrode is operably associated with said oneor more first forming tools, said second RF electrode is operablyassociated with said one or more second forming tools, and the portionof the inner wall of said forming cavity which is adapted to form saiddosage form is insulative to said RF energy.
 7. A machine of claim 1,wherein said first RF electrode is operably associated with said one ormore first forming tools and second RF electrode is operably associatedwith the portion of said inner wall of said one or more forming cavitiesthat is adapted to form said dosage form.
 8. A machine of claim 1,wherein said first RF electrode is operably associated with a firstportion of said inner wall of said one or more forming cavities that isadapted to form said dosage form and second RF electrode is operablyassociated with a second portion of said inner wall of said one or moreforming cavities that is adapted to form said dosage form.
 9. A machineof claim 1, wherein said die block comprises at least six of saidforming cavities.
 10. A machine of claim 1, wherein said first formingtool or said second forming tool is further adapted to eject said tabletfrom said forming cavity.
 11. A machine for the production of a soliddosage form, said machine comprising: (a) a die block having one or moreforming cavities each having an inner wall, a first opening at thesurface of one side of said die block, and a second opening at thesurface on the opposite side of said die block; (b) one or more firstdosing nozzles adapted to both measure an amount of a first powder blendand discharge said measured amount of said first powder blend within oneof said one or more forming cavity; (c) one or more second dosingnozzles adapted to both measure an amount of a second powder blend anddischarge said measured amount of said second powder blend within one ofsaid one or more forming cavity; (d) one or more first forming toolseach adapted to move into one of said cavities through the first openingof said forming cavity; (e) one or more second forming tools eachadapted to move adjacent to one of said second openings or into one ofsaid cavities through the second opening of said forming cavity; (f) atleast one first RF electrode operably associated with said one or morefirst forming tools, said one or more second forming tools, or saidinner wall of said one or more forming cavities; and (g) at least onesecond RF electrode operably associated with said one or more firstforming tools, said one or more second forming tools, or said inner wallof said one or more forming cavities; wherein said machine is adapted toform a dosage form between a first forming tool and a second formingtool within a forming cavity and wherein said first RF electrode andsaid second RF electrode are arranged within said machine such that whenRF energy is applied between said first RF electrode and said second RFelectrode, said RF energy passes through the portion of said formingcavity adapted to form said dosage form.
 12. A machine of claim 11,wherein said one or more first dosing nozzles are adapted to measure anamount of said first powder blend using negative pressure and said oneor more second dosing nozzles are adapted to measure an amount of saidsecond powder blend using negative pressure.
 13. A machine of claim 11,wherein said one or more first dosing nozzles are adapted to dischargesaid measured amount of said first powder blend using positive pressureand said one or more second dosing nozzles are adapted to discharge saidmeasured amount of said second powder blend using positive pressure. 14.A machine of claim 12, wherein said one or more first dosing nozzles areadapted to discharge said measured amount of said first powder blendusing positive pressure and said one or more second dosing nozzles areadapted to discharge said measured amount of said second powder blendusing positive pressure.
 15. A machine if claim 11, wherein said machinefurther comprises an RF energy source in communication with said firstRF electrode and said second RF electrode.
 16. A machine of claim 11,wherein said first RF electrode is operably associated with said one ormore first forming tools, said second RF electrode is operablyassociated with said one or more second forming tools, and the portionof the inner wall of said forming cavity which is adapted to form saiddosage form is insulative to said RF energy.
 17. A machine of claim 11,wherein said first RF electrode is operably associated with said one ormore first forming tools and second RF electrode is operably associatedwith the portion of said inner wall of said one or more forming cavitiesthat is adapted to form said dosage form.
 18. A machine of claim 11,wherein said first RF electrode is operably associated with a firstportion of said inner wall of said one or more forming cavities that isadapted to form said dosage form and second RF electrode is operablyassociated with a second portion of said inner wall of said one or moreforming cavities that is adapted to form said dosage form.
 19. A machineof claim 11, wherein said die block comprises at least six of saidforming cavities.
 20. A machine of claim 11, wherein said first formingtool or said second forming tool is further adapted to eject said tabletfrom said forming cavity.
 21. A machine for the production of a soliddosage form, said machine comprising: (a) a die block having one or moreforming cavities each having an inner wall, a first opening at thesurface of one side of said die block, and a second opening at thesurface on the opposite side of said die block, wherein said formingcavity further comprises a movable divider adapted to form a firstchamber and a second chamber within said forming cavity; (b) one or morefirst dosing nozzle adapted to both measure an amount of a first powderblend and discharge said measured amount of said first powder blendwithin one of said first chamber; (c) one or more second dosing nozzleadapted to both measure an amount of a second powder blend and dischargesaid measured amount of said second powder blend within one of saidsecond chamber; (d) one or more first forming tools each adapted to moveinto one of said cavities through the first opening of said formingcavity; (e) one or more second forming tools each adapted to moveadjacent to one of said second openings or into one of said cavitiesthrough the second opening of said forming cavity; (f) at least onefirst RF electrode operably associated with said one or more firstforming tools, said one or more second forming tools, or said inner wallof said one or more forming cavities; and (g) at least one second RFelectrode operably associated with said one or more first forming tools,said one or more second forming tools, or said inner wall of said one ormore forming cavities; wherein said machine is adapted to remove saidmovable divider from within said forming cavity such that said firstpowder blend contacts said second powder blend within said formingcavity and wherein said first RF electrode and said second RF electrodeare arranged within said machine such that when RF energy is appliedbetween said first RF electrode and said second RF electrode, said RFenergy passes through the portion of said forming cavity adapted to formsaid dosage form.
 22. The machine of claim 21, wherein said movabledivider is curved.